Dumitriu and colleagues have used a new conditional knock-out mouse model for Sox6 to study definitive erythropoiesis in the fetal liver. These studies confirm previous findings with Sox6–/– mice and now demonstrate that EPO receptor–mediated deletion of Sox6 in committed erythroid progenitors is additive with EPO for maturation, proliferation, and survival. This figure demonstrates the increase in nucleated red blood cells, anemia, and increase in erythropoietic tissue volume associated with conditional deletion. Of importance, this approach indicates that Sox6 functions in a cell-intrinsic manner to regulate erythroid development and suggests that Sox6 may be an important new therapeutic target. See the complete figure and table in the article beginning on page 1198.